The fixed-dose mix of ledipasvir-sofosbuvir supplies an effective and well-tolerated one-pill once-a-day alternative for treatment of genotypes 1, 4, 5, and 6 chronic hepatitis C (HCV) infection. This direct-acting antiviral routine was the first FDA-approved interferon- and ribavirin-free routine to treat hepatitis C.
Ledipasvir-sofosbuvir can be used without ribavirin in many patients with genotype 1A, except those who are cirrhotic and treatment-experienced.
In addition, patients who are treatment-naïve, not black, and without cirrhosis might be eligible for an 8-week duration which has actually been discovered in scientific trials and observational studies to be as reliable as 12 weeks. Like sofosbuvir-velpatasvir, the other NS5B-NS5A inhibitor combination, it has been revealed to be safe and efficacious in patients with decompensated cirrhosis.
Class and Mechanism
Ledipasvir is a powerful inhibitor of HCV NS5A, a viral phosphoprotein that plays an essential function in viral replication, assembly, and secretion.
Sofosbuvir is a nucleotide analog inhibitor of liver disease C infection NS5B polymerase– the key enzyme moderating HCV RNA duplication. The triphosphate form of sofosbuvir (GS-461203) mimics the natural cellular uridine nucleotide and is integrated by the HCV RNA polymerase into the elongating RNA primer hair, leading to viral chain termination.
Maker for United States
The fixed-dose combination of ledipasvir and sofosbuvir (Harvoni) is produced by Gilead Sciences.
Cost and Medication Access
The wholesale acquisition cost (WAC) for ledipasvir-sofosbuvir is $1125 per pill.
- Cost of 8-week course of therapy = $63,000.
- Cost of 12-week course of therapy = $94,500.
- Cost of 24-week course of therapy = $189,000.
Info concerning the Gilead Sciences ledipasvir-sofosbuvir (Harvoni) patient support program can be gotten at the Support Path for Solvaldi and Harvoni website and by contacting them directly by phone at 1-855-769-7284 (hours of operation Monday through Friday between 9:00 am and 8:00 pm Eastern Time).
Negative Effects
Readily available information from scientific trials has actually demonstrated the mix of ledipasvir-sofosbuvir has actually been extremely well tolerated. The most typical reported negative impacts are tiredness and headache.
Boxed Warning
CAUTION: RISK OF HEPATITIS B VIRUS REACTIVATION IN PATIENTS COINFECTED WITH HCV AND HBV.
Test all patients for evidence of current or prior liver disease B infection (HBV) infection prior to initiating treatment with HARVONI. HBV reactivation has been reported in HCV/HBV coinfected patients who were going through or had completed treatment with HCV direct acting antivirals and were not getting HBV antiviral therapy. Some cases have resulted in fulminant hepatitis, hepatic failure, and death. Screen HCV/HBV coinfected patients for hepatitis flare or HBV reactivation during HCV treatment and post-treatment follow-up. Initiate proper patient management for HBV infection as scientifically shown.
Indicators and Usage
Adult Patients:
HARVONI is shown for the treatment of adult patients with chronic liver disease C infection (HCV):
- genotype 1, 4, 5, or 6 infection without cirrhosis or with compensated cirrhosis.
- genotype 1 infection with decompensated cirrhosis, for use in mix with ribavirin.
- genotype 1 or 4 infection who are liver transplant recipients without cirrhosis or with compensated cirrhosis, for use in combination with ribavirin.
Pediatric Patients:
HARVONI is indicated for the treatment of pediatric patients 12 years of age and older or weighing at least 35 kg with HCV genotype 1, 4, 5, or 6 infection without cirrhosis or with compensated cirrhosis.
Dose Forms and Strengths
HARVONI is available as an orange colored, diamond formed, film-coated tablet debossed with “GSI” on one side and “7985” on the other side of the tablet. Each tablet consists of 90 mg ledipasvir and 400 mg sofosbuvir.
Contraindications
If HARVONI is administered with ribavirin, the contraindications to ribavirin also apply to this mix regimen. Describe the ribavirin recommending details for a list of contraindications for ribavirin.
Cautions and Precautions
Risk of Hepatitis B Virus Reactivation in Patients Coinfected with HCV and HBV
Hepatitis B virus (HBV) reactivation has been reported in HCV/HBV coinfected patients who were going through or had actually completed treatment with HCV direct acting antivirals, and who were not getting HBV antiviral therapy.
Some cases have led to fulminant liver disease, hepatic failure, and death. Cases have been reported in patients who are HBsAg positive and also in patients with serologic proof of dealt with HBV infection (i.e., HBsAg negative and anti-HBc positive).
HBV reactivation has actually likewise been reported in patients getting particular immunosuppressants or chemotherapeutic agents; the risk of HBV reactivation related to treatment with HCV direct-acting antivirals may be increased in these patients.
HBV reactivation is characterized as an abrupt increase in HBV replication manifesting as a quick increase in serum HBV DNA level.
In patients with fixed HBV infection, reappearance of HBsAg can occur. Reactivation of HBV duplication may be accompanied by hepatitis, i.e., increases in aminotransferase levels and, in severe cases, increases in bilirubin levels, liver failure, and death can happen.
Test all patients for proof of present or previous HBV infection by measuring HBsAg and anti-HBc before initiating HCV treatment with HARVONI.
In patients with serologic proof of HBV infection, monitor for clinical and laboratory signs of liver disease flare or HBV reactivation during HCV treatment with HARVONI and during post-treatment follow-up. Start proper patient management for HBV infection as medically suggested.
Serious Symptomatic Bradycardia When Coadministered with Amiodarone
Postmarketing cases of symptomatic bradycardia, in addition to fatal cardiac arrest and cases requiring pacemaker intervention, have been reported when amiodarone is coadministered with HARVONI.
Bradycardia has actually normally happened within hours to days, however cases have been observed approximately 2 weeks after initiating HCV treatment.
Patients also taking beta blockers, or those with underlying cardiac comorbidities and/or advanced liver disease, might be at increased risk for symptomatic bradycardia with coadministration of amiodarone. Bradycardia typically fixed after discontinuation of HCV treatment. The mechanism for this result is unidentified.
Coadministration of amiodarone with HARVONI is not suggested. For patients taking amiodarone who have no other alternative, viable treatment choices and who will be coadministered HARVONI:
- Counsel patients about the risk of serious symptomatic bradycardia.
- Heart monitoring in an in-patient setting for the first 2 Days of coadministration is suggested, after which outpatient or self-monitoring of the heart rate should happen on a daily basis through a minimum of the first 2 weeks of treatment.
Patients who are taking HARVONI who have to begin amiodarone therapy due to no other option, viable treatment choices ought to go through similar cardiac monitoring as described above.
Due to amiodarone’s long half-life, patients ceasing amiodarone just prior to starting HARVONI must likewise undergo comparable cardiac tracking as laid out above.
Patients who develop signs or symptoms of bradycardia ought to look for medical examination immediately.
Symptoms may include near-fainting or fainting, dizziness or lightheadedness, despair, weakness, extreme fatigue, shortness of breath, chest pains, confusion or memory problems.
Risk of Reduced Therapeutic Effect Due to Use with P-gp Inducers
The concomitant use of HARVONI and P-gp inducers (e.g., rifampin, St. John’s wort) may substantially decrease ledipasvir and sofosbuvir plasma concentrations and may cause a minimized restorative impact of HARVONI. For that reason, using HARVONI with P-gp inducers (e.g., rifampin or St. John’s wort) is not suggested.
Risks Associated with Ribavirin Combination Treatment
If HARVONI is administered with ribavirin, the warnings and preventative measures for ribavirin, in specific the pregnancy avoidance warning, use to this combination routine. Refer to the ribavirin recommending details for a full list of the warnings and precautions for ribavirin.
Adverse Responses
The following serious unfavorable responses are explained below and elsewhere in labeling:
Serious Symptomatic Bradycardia When Coadministered with Amiodarone.
Clinical Trials Experience
Because medical trials are carried out under commonly varying conditions, negative reaction rates observed in the medical trials of a drug can not be directly compared with rates in the scientific trials of another drug and might not reflect the rates observed in practice.
If HARVONI is administered with ribavirin to adults, refer to the recommending details for ribavirin for a description of ribavirin-associated negative reactions.
Scientific Trials in Adult Subjects
The safety assessment of HARVONI was based on pooled information from three randomized, open-label Phase 3 clinical trials (ION-3, ION-1, and ION-2) of topics with genotype 1 HCV with compensated liver disease (with and without cirrhosis) including 215, 539, and 326 topics who received HARVONI daily by mouth for 8, 12 and 24 weeks, respectively.
The proportion of topics who permanently ceased treatment due to negative occasions was 0%, less than 1%, and 1% for subjects getting HARVONI for 8, 12, and 24 weeks, respectively.
The most typical negative reactions (at least 10%) were tiredness and headache in topics treated with 8, 12, or 24 weeks of HARVONI.
The safety evaluation of HARVONI was also based upon pooled data from 3 open-label trials (Study 1119, ION-4, and ELECTRON-2) in 118 topics with chronic HCV genotype 4, 5, or 6 infection with compensated liver disease (with or without cirrhosis) [see Clinical Studies (14.3)] The topics received HARVONI once daily by mouth for 12 weeks. The safety profile in topics with chronic HCV genotype 4, 5, or 6 infection with compensated liver disease resembled that observed in topics with chronic HCV genotype 1 infection with compensated liver disease. The most common unfavorable responses happening in at least 10% of topics were asthenia (18%), headache (14%), and fatigue (10%).
Unfavorable Reactions in Subjects with Cirrhosis
The safety evaluation of HARVONI with or without ribavirin was based on a randomized, double-blind and placebo-controlled trial in treatment-experienced genotype 1 subjects with compensated cirrhosis and was compared with placebo.
Subjects were randomized to receive 24 weeks of HARVONI daily by mouth without ribavirin or 12 weeks of placebo followed by 12 weeks of HARVONI daily by mouth + ribavirin.
As defined above, that accompanied a minimum of 5% greater frequency in subjects treated with 24 weeks of HARVONI or 12 weeks of HARVONI + ribavirin, compared to those reported for 12 weeks of placebo. The majority of the negative reactions were Grade 1 or 2 in severity.
Unfavorable Reactions in Subjects Coinfected with HIV-1
The safety assessment of HARVONI was based upon an open-label clinical trial in 335 genotype 1 or 4 topics with HCV/HIV -1 coinfection who were on steady antiretroviral therapy in Study ION-4.
The safety profile in HCV/HIV -1 coinfected subjects resembled that observed in HCV mono-infected subjects. The most typical adverse reactions taking place in at least 10% of topics were headache (20%) and tiredness (17%).
Adverse Reactions in Liver Transplant Recipients and/or Subjects with Decompensated Cirrhosis
The safety evaluation of HARVONI with ribavirin (RBV) in liver transplant recipients and/or those who had actually decompensated liver disease was based on pooled data from two Phase 2 open-label medical trials including 336 topics who got HARVONI plus RBV for 12 weeks. Topics with Child-Pugh-Turcotte (CPT) scores greater than 12 were omitted from the trials.
The unfavorable occasions observed followed the expected scientific sequelae of liver transplant and/or decompensated liver disease, or the known safety profile of HARVONI and/or ribavirin.
Reduces in hemoglobin to less than 10 g/dL and 8.5 g/dL during treatment were observed in 38% and 13% of topics treated with HARVONI plus RBV for 12 weeks, respectively. Ribavirin was completely terminated in 11% of topics treated with HARVONI plus RBV for 12 weeks.
Liver Transplant Recipients with Compensated Liver Disease
Amongst the 174 liver transplant receivers with compensated liver disease who received HARVONI with RBV for 12 weeks, 2 (1%) topics permanently discontinued HARVONI due to an unfavorable occasion.
Subjects with Decompensated Liver Disease
Amongst the 162 topics with decompensated liver disease (pre- or post-transplant) who got HARVONI with RBV for 12 weeks, 7 (4%) subjects died, 4 (2%) topics went through liver transplant, and 1 topic (< 1%) went through liver hair transplant and died during treatment or within 30 days after discontinuation of treatment.
Due to the fact that these events occurred in patients with advanced liver disease who are at risk of development of liver disease consisting of liver failure and death, it is not possible to dependably assess the contribution of drug impact to outcomes. A total of 4 (2%) subjects permanently terminated HARVONI due to an adverse occasion.
Less Common Adverse Reactions Reported in Clinical Trials (less than 5%): The following adverse responses took place in less than 5% of topics receiving HARVONI in any one trial. These occasions have been consisted of since of their seriousness or assessment of possible causal relationship.
Psychiatric disorders: depression (including in topics with pre-existing history of psychiatric disease).
Depression (particularly in subjects with pre-existing history of psychiatric disease) happened in topics receiving sofosbuvir containing routines. Self-destructive ideation and suicide have taken place in less than 1% of topics treated with sofosbuvir in mix with ribavirin or pegylated interferon/ribavirin in other clinical trials.
Lab Abnormalities
Bilirubin Elevations: Bilirubin elevations of greater than 1.5 × ULN were observed in 3%, less than 1%, and 2% of topics treated with HARVONI for 8, 12, and 24 weeks, respectively.
Bilirubin elevations of higher than 1.5 × ULN were observed in 3%, 11%, and 3% of topics with compensated cirrhosis treated with placebo, HARVONI + ribavirin for 12 weeks and HARVONI for 24 weeks, respectively, in the SIRIUS trial.
Lipase Elevations: Transient, asymptomatic lipase elevations of higher than 3 × ULN were observed in less than 1%, 2%, and 3% of topics treated with HARVONI for 8, 12, and 24 weeks, respectively.
Transient, asymptomatic lipase elevations of higher than 3 × ULN were observed in 1%, 3%, and 9% of topics with compensated cirrhosis treated with placebo, HARVONI + ribavirin for 12 weeks, and HARVONI for 24 weeks, respectively.
Creatine Kinase: Creatine kinase was not examined in Phase 3 trials ION-3, ION-1, or ION-2 of HARVONI. Creatine kinase was examined in the ION-4 trial. Isolated, asymptomatic creatine kinase elevations of higher than or equivalent to 10 × ULN was observed in 1% of topics treated with HARVONI for 12 weeks in the ION-4 trial and has actually also been formerly reported in topics treated with sofosbuvir in mix with ribavirin or peginterferon/ribavirin in other clinical trials.
Unfavorable Reactions in Pediatric Subjects 12 Years of Age and Older
The safety assessment of HARVONI in pediatric subjects 12 years of age and older is based on information from a Phase 2, open-label clinical trial that registered 100 topics without cirrhosis or with compensated cirrhosis who were treated with HARVONI for 12 weeks.
The unfavorable responses observed followed those observed in medical studies of HARVONI in adults. Restricted safety data are available in pediatric topics getting HARVONI for 24 weeks. No Grade 3 or 4 negative reactions or discontinuation due to a negative response was observed in those pediatric subjects getting HARVONI for 24 weeks.
Postmarketing Experience
The following unfavorable responses have been identified during post approval use of HARVONI. Because postmarketing reactions are reported willingly from a population of uncertain size, it is not constantly possible to dependably approximate their frequency or develop a causal relationship to drug direct exposure.
- Heart Disorders
Serious symptomatic bradycardia has actually been reported in patients taking amiodarone who initiate treatment with HARVONI.
- Skin and Subcutaneous Tissue Disorders
Skin rashes, sometimes with blisters or angioedema-like swelling.
Angioedema.
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